Introduction: Beyond Genetics
- Levin’s group studies how evolution uses a “multiscale competency architecture” and focuses on the “software” level (bioelectricity) rather than just the “hardware” (DNA).
- Biology utilizes “agential materials”: Cells have inherent goals and problem-solving abilities, not just passive components.
- Dynamic, robust anatomical homeostasis is a form of cellular collective intelligence, problem-solving in “morphospace.”
- Developmental bioelectricity is a key “cognitive glue” coordinating cells to achieve large-scale anatomical outcomes.
The “Anatomical Compiler” – A Regenerative Medicine Goal
- The long-term goal is an “anatomical compiler”: Software to translate a desired anatomical design into stimuli that guide cells to build it.
- This would solve major medical problems like birth defects, injury, cancer, and aging by controlling cell group construction.
- Current limitations: We lack models to predict anatomy from genomes alone, even in chimeric embryos (e.g., axolotl-frog hybrids).
- Medicine focuses on “hardware” (genetics, pathways); understanding “software” (cellular decision-making) is crucial, especially in novel situations.
Cellular Intelligence and Robust Development
- Embryogenesis isn’t hardwired: Cutting an embryo in half yields two normal individuals, showing adaptability.
- Cells adjust to internal changes: Kidney tubule cells adapt to varying sizes, maintaining correct lumen diameter through different mechanisms.
- Regeneration demonstrates anatomical homeostasis: A salamander limb regrows to the correct size and stops.
- “Picasso tadpoles” with misplaced facial features develop into mostly normal frogs, demonstrating error correction.
- Cells form networks, scaling up homeostatic loops. Single-cell goals (pH, hunger) expand to tissue/organ goals (limb length, finger count). Cancer involves cells reverting to primitive, single-cell goals.
Bioelectricity: The Cellular Communication Network
- Cells use bioelectricity, like brains, but predating nervous systems: Ion channels create voltage potentials; electrical synapses (gap junctions) facilitate communication.
- Early embryos use electrical networks to guide body plan development in “morphospace.”
- Levin’s group manipulates bioelectricity *without* external fields or electrodes, but through ion channel modulation (optogenetics, drugs, mutations) and gap junction control.
- Cancer cells disconnect electrically from neighbors. Forcing connection via ion channel expression can prevent tumor formation despite oncogene presence.
- The “electric face” of frog embryos prefigures facial structure, showing a bioelectric memory of the correct form. Disrupting it causes mispatterning.
- Ectopic organs (eyes, legs) can be induced by rewriting the bioelectric pattern in cells, acting as a modular “subroutine call.” Cells also recruit neighbors.
Brain Defect Repair and Planaria’s “Memories”
- A bioelectric pre-pattern determines early brain shape. Computational models guide ion channel manipulation (e.g., hcn2) to restore the pattern and correct brain defects caused by teratogens.
- Planaria (flatworms) regenerate any body part.
- Bioelectric patterns store a stable “memory” of the number of heads. Altering this (without genetic changes) creates two-headed worms.
- This altered body plan is stable through multiple cuttings, demonstrating a non-genetic, rewritable, long-term memory, analogous to incepting false memories.
- Planaria’s bioelectric circuits have multiple stable states. Work is being undertaken on the State Space and the merging formalizations between Electrical Cirtuits, Formalisms and Connectionist Architechtures
- Machine learning helps infer circuits and interventions for bioelectric control.
- Planaria can be induced to grow heads of *other* species by manipulating electrical communication, demonstrating plasticity beyond their genome’s usual expression.
Xenobots: New Life Forms From Frog Cells
- “Xenobots” are novel proto-organisms created from frog skin cells, with the *same* genome as tadpoles.
- Removed from the normal embryonic context, these cells exhibit novel behaviors and a new developmental sequence *without* eons of selection.
- This highlights the inherent potential of cells to explore “morphospace” and form new structures when constraints are removed, exploring new problems and how groups of cells could collectively adapt.